tbuckley/cabot-search huggingface dataset:
Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer
Authors: Karla Rubio, Addi J. Romero-Olmedo, Pouya Sarvari, Guruprasadh Swaminathan, Vikas P. Ranvir, Diana G. Rogel-Ayala, Julio Cordero, Stefan Günther, Aditi Mehta, Birgit Bassaly, Peter Braubach, Malgorzata Wygrecka, Stefan Gattenlöhner, Achim Tresch, Thomas Braun, Gergana Dobreva, Miguel N. Rivera, Indrabahadur Singh, Johannes Graumann, Guillermo Barreto
Journal: Theranostics (2023)

Background: Small cell lung cancer (SCLC) is an extremely aggressive cancer type with a patient median survival of 6-12 months.Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC.In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways.However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC remains elusive.Methods: We analyzed human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines by classical methods of molecular biology and biochemistry.In addition, we performed RNA-sequencing-based transcriptomic analysis in human lung cancer cells and human lung tissue samples, as well as high-resolution mass spectrometric analysis of the protein cargo from extracellular vesicles (EVs) that were isolated from human lung cancer cells. Ivyspring
Neighborhood Income Mobility and Risk of Neonatal and Maternal Morbidity
Authors: Jennifer A. Jairam, Simone N. Vigod, Arjumand Siddiqi, Jun Guan, Alexa Boblitz, Xuesong Wang, Patricia O’Campo, Joel G. Ray
Journal: JAMA Network Open (2023)

Importance Residing in a low-income neighborhood is generally associated with worse pregnancy outcomes. It is not known if moving from a low- to higher-income area between 2 pregnancies alters the risk of adverse birth outcomes in the subsequent birth compared with women who remain in low-income areas for both births. Objective To compare the risk of adverse maternal and newborn outcomes among women who achieved upward area-level income mobility vs those who did not. Design, Setting, and Participants This population-based cohort study was completed in Ontario, Canada, from 2002 to 2019, where there is universal health care. Included were all nulliparous women with a first-time singleton birth at 20 to 42 weeks’ gestation, each residing in a low-income urban neighborhood at the time of the first birth. All women were then assessed at their second birth. Statistical analysis was conducted from August 2022 to April 2023. Exposure Movement from a lowest-income quintile (Q1) neighborhood to any higher-income quintile neighborhood (Q2-Q5) between the first and second birth. Main Outcomes and Measures The maternal outcome was severe maternal morbidity or mortality (SMM-M) at the second birth hospitalization or up to 42 days post partum. The primary perinatal outcome was severe neonatal morbidity or mortality (SNM-M) within 27 days of the second birth. Relative risks (aRR) and absolute risk differences (aARD) were estimated by adjusting for maternal and infant characteristics. Results A total of 42 208 (44.1%) women (mean [SD] age at second birth, 30.0 [5.2] years) experienced upward area-level income mobility, and 53 409 (55.9%) women (age at second birth, 29.0 [5.4] years) remained in income Q1 between births. Relative to women who remained in income Q1 between births, those with upward mobility had a lower associated risk of SMM-M (12.0 vs 13.3 per 1000 births), with an aRR of 0.86 (95% CI, 0.78 to 0.93) and aARD of −2.09 per 1000 (95% CI, −3.1 to −0.9 per 1000 ). Likewise, their newborns experienced lower respective rates of SNM-M (48.0 vs 50.9 per 1000 live births), with an aRR of 0.91 (95% CI, 0.87 to 0.95) and aARD of −4.7 per 1000 (95% CI, −6.8 to −2.6 per 1000). Conclusions and Relevance In this cohort study of nulliparous women living in low-income areas, those who moved to a higher-income area between births experienced less morbidity and death in their second pregnancy, as did their newborns, compared with those who remained in low-income areas between births. Research is needed to determine whether financial incentives or enhancement of neighborhood factors can reduce adverse maternal and perinatal outcomes.
<i>PIK3CA</i> Mutations Are an Early Genetic Alteration Associated with <i>FGFR3</i> Mutations in Superficial Papillary Bladder Tumors
Authors: Elena López-Knowles, Silvia Hernández, Núria Malats, Manolis Kogevinas, Josep Lloreta, Alfredo Carrato, Adonina Tardón, Consol Serra, Francisco X. Real
Journal: Cancer Research (2006)

Abstract Bladder tumors constitute a very heterogeneous disease. Superficial tumors are characterized by a high prevalence of FGFR3 mutations and chromosome 9 alterations. High-grade and muscle-invasive tumors are characterized by Tp53 mutations and aneuploidy. We have analyzed the sequence of exons 9 and 20 of PIK3CA in a panel of bladder tumors covering the whole spectrum of the disease. DNA from formalin-fixed, paraffin-embedded tumor sections was amplified by PCR and products were sequenced. In an unselected panel of tumors representative of the disease, the PIK3CA mutation prevalence was 13% (11 of 87). Mutations occurred mainly at the previously identified hotspots (codons 542, 545, 1007, and 1047). The distribution according to stage was as follows: papillary urothelial neoplasms of uncertain malignant potential (PUNLMP; 11 of 43, 25.6%), Ta (9 of 57, 16%), T1 (2 of 10, 20%), and muscle-invasive tumors (0 of 20, 0%; P = 0.019). Mutations were associated with low-grade tumors: grade 1 (6 of 27, 22.2%), grade 2 (3 of 23, 13%), and grade 3 (2 of 37, 5.4%; P = 0.047). Overall, PIK3CA mutations were strongly associated with FGFR3 mutations: 18 of 69 (26%) FGFR3mut tumors were PIK3CAmut, versus 4 of 58 (6.9%) FGFR3wt tumors (P = 0.005). Our findings indicate that PIK3CA mutations are a common event that can occur early in bladder carcinogenesis and support the notion that papillary and muscle-invasive tumors arise through different molecular pathways. PIK3CA may constitute a novel diagnostic and prognostic tool, as well as a therapeutic target, in bladder cancer. (Cancer Res 2006; 66(15): 7401-4)
Interpreting cancer incidence trends: challenges due to the COVID-19 pandemic
Authors: Angela B Mariotto, Eric J Feuer, Nadia Howlader, Huann-Sheng Chen, Serban Negoita, Kathleen A Cronin
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract The considerable deficit in cancer diagnoses in 2020 due to COVID-19 pandemic disruptions in health care can pose challenges in the estimation and interpretation of long-term cancer trends. Using Surveillance, Epidemiology, and End Results (SEER) (2000-2020) data, we demonstrate that inclusion of the 2020 incidence rates in joinpoint models to estimate trends can result in a poorer fit to the data and less accurate or less precise trend estimates, providing challenges in the interpretation of the estimates as a cancer control measure. To measure the decline in 2020 relative to 2019 cancer incidence rates, we used the percent change of rates in 2020 compared with 2019. Overall, SEER cancer incidence rates dropped approximately 10% in 2020, but for thyroid cancer the decrease was as large as 18% after adjusting for reporting delay. The 2020 SEER incidence data are available in all SEER released products, except for joinpoint estimates of trends and lifetime risk of developing cancer.
Effect of Vidarabine on Chronic Hepatitis B Virus Infection
Authors: Richard B. Pollard
Journal: JAMA (1978)

SERA of patients with hepatitis B virus (HBV) infection contain several viral forms. The development of reproducible assays for these markers facilitates the evaluation of intervention with antiviral agents. Human leukocyte interferon, given systemically to patients with chronic HBV infection, resulted in a decrease in the Dane particle markers core antigen (HB<sub>c</sub>Ag), DNA polymerase, and the e antigen (HB<sub>e</sub>Ag) to undetectable levels in the serum.<sup>1</sup>The hepatitis B surface antigen (HB<sub>s</sub>Ag) level also decreased in two interferon-treated patients. Vidarabine (adenine arabinoside), a purine nucleoside that inhibits replication of certain DNA viruses in tissue culture, has been administered to humans in an attempt to alter the course of various herpesvirus infections. Herpes simplex encephalitis patients treated with vidarabine had a significantly reduced mortality in a recent report.<sup>2</sup>Toxic reactions with this agent have been minimal at the dosage used in the reported studies.
The Fitness Effects of Codon Composition of the Horizontally Transferred Antibiotic Resistance Genes Intensify at Sub-lethal Antibiotic Levels
Authors: Michael Shaferman, Melis Gencel, Noga Alon, Khawla Alasad, Barak Rotblat, Adrian W R Serohijos, Lital Alfonta, Shimon Bershtein
Journal: Molecular Biology and Evolution (2023)

Abstract The rampant variability in codon bias existing between bacterial genomes is expected to interfere with horizontal gene transfer (HGT), a phenomenon that drives bacterial adaptation. However, delineating the constraints imposed by codon bias on functional integration of the transferred genes is complicated by multiple genomic and functional barriers controlling HGT, and by the dependence of the evolutionary outcomes of HGT on the host's environment. Here, we designed an experimental system in which codon composition of the transferred genes is the only variable triggering fitness change of the host. We replaced Escherichia coli's chromosomal folA gene encoding dihydrofolate reductase, an essential enzyme that constitutes a target for trimethoprim, with combinatorial libraries of synonymous codons of folA genes from trimethoprim-sensitive Listeria grayi and trimethoprim-resistant Neisseria sicca. The resulting populations underwent selection at a range of trimethoprim concentrations, and the ensuing changes in variant frequencies were used to infer the fitness effects of the individual combinations of codons. We found that when HGT causes overstabilization of the 5′-end mRNA, the fitness contribution of mRNA folding stability dominates over that of codon optimality. The 5′-end overstabilization can also lead to mRNA accumulation outside of the polysome, thus preventing the decay of the foreign transcripts despite the codon composition-driven reduction in translation efficiency. Importantly, the fitness effects of mRNA stability or codon optimality become apparent only at sub-lethal levels of trimethoprim individually tailored for each library, emphasizing the central role of the host's environment in shaping the codon bias compatibility of horizontally transferred genes.
Supramolecular Fibrous Hydrogel Augmentation of Uterosacral Ligament Suspension for Treatment of Pelvic Organ Prolapse
Authors: Beverly Miller, Wiley Wolfe, James L. Gentry, M. Gregory Grewal, Christopher B. Highley, Raffaella De Vita, Monique H. Vaughan, Steven R. Caliari
Journal: Advanced Healthcare Materials (2023)

Abstract Uterosacral ligament suspension (USLS) is a common surgical treatment for pelvic organ prolapse (POP). However, the relatively high failure rate of up to 40% underscores a strong clinical need for complementary treatment strategies, such as biomaterial augmentation. Herein, the first hydrogel biomaterial augmentation of USLS in a recently established rat model is described using an injectable fibrous hydrogel composite. Supramolecularly‐assembled hyaluronic acid (HA) hydrogel nanofibers encapsulated in a matrix metalloproteinase (MMP)‐degradable HA hydrogel create an injectable scaffold showing excellent biocompatibility and hemocompatibility. The hydrogel can be successfully delivered and localized to the suture sites of the USLS procedure, where it gradually degrades over six weeks. In situ mechanical testing 24 weeks post‐operative in the multiparous USLS rat model shows the ultimate load (load at failure) to be 1.70 ± 0.36 N for the intact uterosacral ligament (USL), 0.89 ± 0.28 N for the USLS repair, and 1.37 ± 0.31 N for the USLS + hydrogel (USLS+H) repair ( n = 8). These results indicate that the hydrogel composite significantly improves load required for tissue failure compared to the standard USLS, even after the hydrogel degrades, and that this hydrogel‐based approach can potentially reduce the high failure rate associated with USLS procedures.
NHS reviews abuse of staff and patients, as legal bill exceeds £82m in five years
Authors: Adele Waters, Ingrid Torjesen
Journal: BMJ (2023)

The NHS is conducting an urgent review into physical and sexual abuse of staff on NHS premises, with recommendations expected in the autumn. News of the review came as an investigation byThe BMJ and the Guardian showed "shocking" levels of sexual abuse taking place on NHS premises. 1The investigation found that 35 606 incidents of rape, sexual assault, harassment, stalking, and abusive remarks had occurred over five years (2017 to 2022), with most (58%) being cases of patients abusing staff and 20% patients abusing other patients.Nearly three quarters of incidents occurred in mental health trusts.
Vanillin-based functionalization strategy to construct multifunctional microspheres for treating inflammation and regenerating intervertebral disc
Authors: Zhuang Zhu, Qifan Yu, Hanwen Li, Feng Han, Qianping Guo, Heng Sun, He Zhao, Zhengdong Tu, Zhuang Liu, Caihong Zhu, Bin Li
Journal: Bioactive Materials (2023)

Intervertebral disc degeneration (IVDD) is one of the main causes of low back pain. Although local delivery strategies using biomaterial carriers have shown potential for IVDD treatment, it remains challenging for intervention against multiple adverse contributors by a single delivery platform. In the present work, we propose a new functionalization strategy using vanillin, a natural molecule with anti-inflammatory and antioxidant properties, to develop multifunctional gelatin methacrylate (GelMA) microspheres for local delivery of transforming growth factor β3 (TGFβ3) toward IVDD treatment. In vitro, functionalized microspheres not only improved the release kinetics of TGFβ3 but also effectively inhibited inflammatory responses and promoted the secretion of extracellular matrix (ECM) in lipopolysaccharide-induced nucleus pulposus (NP) cells. In vivo, functionalized platform plays roles in alleviating inflammation and oxidative stress, preserving the water content of NP and disc height, and maintaining intact structure and biomechanical functions, thereby promoting the regeneration of IVD. High-throughput sequencing suggests that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt signaling might be associated with their therapeutic effects. In summary, the vanillin-based functionalization strategy provides a novel and simple way for packaging multiple functions into a single delivery platform and holds promise for tissue regeneration beyond the IVD.
Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors
Authors: In-Young Jung, Estela Noguera-Ortega, Robert Bartoszek, Sierra M. Collins, Erik Williams, Megan Davis, Julie K. Jadlowsky, Gabriela Plesa, Donald L. Siegel, Anne Chew, Bruce L. Levine, Shelley L. Berger, Edmund K. Moon, Steven M. Albelda, Joseph A. Fraietta
Journal: Cell Reports Medicine (2023)

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-T
An Ancestral Balanced Inversion Polymorphism Confers Global Adaptation
Authors: Martin Kapun, Esra Durmaz Mitchell, Tadeusz J Kawecki, Paul Schmidt, Thomas Flatt
Journal: Molecular Biology and Evolution (2023)

Abstract Since the pioneering work of Dobzhansky in the 1930s and 1940s, many chromosomal inversions have been identified, but how they contribute to adaptation remains poorly understood. In Drosophila melanogaster, the widespread inversion polymorphism In(3R)Payne underpins latitudinal clines in fitness traits on multiple continents. Here, we use single-individual whole-genome sequencing, transcriptomics, and published sequencing data to study the population genomics of this inversion on four continents: in its ancestral African range and in derived populations in Europe, North America, and Australia. Our results confirm that this inversion originated in sub-Saharan Africa and subsequently became cosmopolitan; we observe marked monophyletic divergence of inverted and noninverted karyotypes, with some substructure among inverted chromosomes between continents. Despite divergent evolution of this inversion since its out-of-Africa migration, derived non-African populations exhibit similar patterns of long-range linkage disequilibrium between the inversion breakpoints and major peaks of divergence in its center, consistent with balancing selection and suggesting that the inversion harbors alleles that are maintained by selection on several continents. Using RNA-sequencing, we identify overlap between inversion-linked single-nucleotide polymorphisms and loci that are differentially expressed between inverted and noninverted chromosomes. Expression levels are higher for inverted chromosomes at low temperature, suggesting loss of buffering or compensatory plasticity and consistent with higher inversion frequency in warm climates. Our results suggest that this ancestrally tropical balanced polymorphism spread around the world and became latitudinally assorted along similar but independent climatic gradients, always being frequent in subtropical/tropical areas but rare or absent in temperate climates.
Towards understandings of serine/arginine-rich splicing factors
Authors: Dianyang Li, Wenying Yu, Maode Lai
Journal: Acta Pharmaceutica Sinica B (2023)

Serine/arginine-rich splicing factors (SRSFs) refer to twelve RNA-binding proteins which regulate splice site recognition and spliceosome assembly during precursor messenger RNA splicing. SRSFs also participate in other RNA metabolic events, such as transcription, translation and nonsense-mediated decay, during their shuttling between nucleus and cytoplasm, making them indispensable for genome diversity and cellular activity. Of note, aberrant SRSF expression and/or mutations elicit fallacies in gene splicing, leading to the generation of pathogenic gene and protein isoforms, which highlights the therapeutic potential of targeting SRSF to treat diseases. In this review, we updated current understanding of SRSF structures and functions in RNA metabolism. Next, we analyzed SRSF-induced aberrant gene expression and their pathogenic outcomes in cancers and non-tumor diseases. The development of some well-characterized SRSF inhibitors was discussed in detail. We hope this review will contribute to future studies of SRSF functions and drug development targeting SRSFs.
Programmed Death Ligand‐1‐Overexpressing Donor Exosomes Mediate Donor‐Specific Immunosuppression by Delivering Co‐Inhibitory Signals to Donor‐Specific T Cells
Authors: Xuewei Luo, Guicheng Du, Yufei Long, Mengchao Zheng, Bingye Chen, Weiting Li, Guoliang Yan, Zhongquan Qi, Tianshu Lan
Journal: Advanced Healthcare Materials (2023)

Programmed death ligand-1 (PD-L1) and donor antigens are critical for donor immature dendritic cells (DCs) targeting donor-specific T cells to induce transplant tolerance. This study aims to clarify whether DC-derived exosomes (DEX) with donor antigens (H2b) and high levels of PD-L1 expression (DEXPDL1+ ) can help to suppress graft rejection. In this study, it is demonstrated that DEXPDL1+ presents donor antigens, as well as PD-L1 co-inhibitory signals, directly or semi-directly via DCs to H2b-reactive T cells. This dual signal presentation can prolong the survival of heart grafts from B6 (H2b) mice but not from C3H (H2k) mice by inhibiting T cell activation, inducing activated T cell apoptosis, and modulating the balance of T cell differentiation from inflammatory to regulatory. Additionally, even though DEXPDL1+ treatment cannot induce tolerance after short-term treatment, this study provides a new vehicle for presenting co-inhibitory signals to donor-specific T cells. This novel strategy may facilitate the realization of donor-specific tolerance via the further optimization of drug-loading combinations and therapeutic regimens to elevate their killing ability.
ECMO: What Would a Deliberative Public Judge?
Authors: Leonard Michael Fleck
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:From Bridge to Destination? Ethical Considerations Related to Withdrawal of ECMO Support over the Objections of Capacitated Patients Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Community Engagement and the Protection-Inclusion Dilemma
Authors: Rebekah McWhirter, Azure Hermes, Sharon Huebner, Alex Brown
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:IRBs and the Protection-Inclusion Dilemma: Finding a Balance Additional informationFundingThis work is supported by National Health and Medical Research Council Synergy [Grant 2011277], Medical Research Future Fund Genomics Health Futures Mission [Grant 2016124], and Australian Research Council Discovery Early Career Research Award DE220101048.
Ethical Withdrawal of ECMO Support Over the Objections of Competent Patients
Authors: Dominic Wilkinson, John Fraser, Jacky Suen, Mioko Kasagi Suzuki, Julian Savulescu
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:From Bridge to Destination? Ethical Considerations Related to Withdrawal of ECMO Support over the Objections of Capacitated Patients DISCLOSURE STATEMENTJohn Fraser has acted as a consultant for De Motu Cordis, is employed by St Andrews War Memorial Hospital as Director of Intensive Care, and by Queensland Health as Director of the Critical Care Research Group, University of Queensland and the Prince Charles Hospital, Brisbane. He has received reimbursements from Disher and Paykel for travel and accommodation to attend medical conference, honoraria from PENN Medicine EMCO/MCS for Symposium keynote, and reimbursement from Gordon Research Institute for registration at Graft Preservation in Heart Transplantation. Julian Savulescu is an ethics consultant for Avon Cosmetics Ltd (2021–2023) and a Bioethics Committee consultant for Bayer.Additional informationFundingThis research was funded in whole, or in part, by the Wellcome Trust [203132/Z/16/Z]. The funders had no role in the preparation of this manuscript or the decision to submit for publication.
Bridge or Destination: Ethical Complexity, Emotional Unrest
Authors: Joel Frader, Erin Paquette, Kelly Michelson, Elaine Morgan
Journal: The American Journal of Bioethics (2023)

Click to increase image sizeClick to decrease image sizeThis article refers to:From Bridge to Destination? Ethical Considerations Related to Withdrawal of ECMO Support over the Objections of Capacitated Patients ACKNOWLEDGEMENTSWe thank the members of the Ethics Advisory Board of the Ann & Robert H. Lurie Children’s Hospital of Chicago who participated in ethics consultation for and discussion of the case that prompted this commentary. We want to extend a particular thank you to our patient and their family members for allowing us to share something of their story.DISCLOSURE STATEMENTNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.